Regional lymph node metastasis is one of the important indicators of cutaneous malignant melanoma. Newly formed lymphatic vessels are considered to provide a route whereby tumor cells can migrate to the lymph nodes. Both vascular endothelial growth factors (VEGF) -C and -D have been confirmed to participate in tumor lymphangiogenesis, but the prognostic significance of VEGF-C, VEGF-D, and lymphangiogenesis in cutaneous malignant melanoma remains controversial. To clarify the effects of these factors and to evaluate the relationships between lymphangiogenesis, lymph node metastasis, and prognosis in patients with malignant melanoma, the expressions of VEGF-C, VEGF-D, and their receptor (VEGFR) -3 were detected by immunohistochemistry and reverse transcriptase-polymerase chain reaction. The expressions of both VEGF-C and VEGF-D proteins were concomitantly detected in the cytoplasm of the malignant cells. VEGF-C and VEGF-D expressions were associated with VEGFR-3 expression and were significantly correlated with both peritumoral lymphangiogenesis and lymph node metastasis. The incidence of peritumoral lymphatic vessels was significantly higher in lymph node metastatic melanomas than that in nonmetastatic melanomas. Univariate and multivariate analyses indicated that VEGF-C and VEGF-D were independent prognostic factors for overall survival and disease-free survival in patients with malignant melanoma. This study suggests that both VEGF-C and VEGF-D are involved in peritumoral lymphangiogenesis and lymphatic metastasis. VEGF-C and VEGF-D expression may be clinically useful indicators for prognostic evaluation in patients with cutaneous malignant melanoma. Anat Rec, 2008. © 2008 Wiley-Liss, Inc.